Spinal cord homeostatic plasticity gates mechanical allodynia in chronic pain

Abstract

Central sensitization caused by disinhibition of spinal cord circuits is a key mechanism of mechanical allodynia in neuropathic pain. Despite intense efforts, the molecular mechanisms that drive disinhibition and induce allodynia after peripheral nerve injury remain unclear. Using the spared-nerve injury (SNI) model of allodynia, we here demonstrate that SNI induces disinhibition of spinal nociceptive circuits by triggering homeostatic synaptic plasticity. Specifically, SNI-triggered homeostatic plasticity suppresses the inhibitory outputs of parvalbumin-positive (PV+) interneurons that form synapses on both primary afferent terminals and excitatory interneurons, causing hyperactivation of the nociceptive pathway. Using genetic manipulations, we identified the retinoic acid receptor RARα as the key mediator of the homeostatic synaptic plasticity underlying this synaptic disinhibition. Deletion of RARα in PV+ neurons blocked SNI-induced spinal disinhibition, central sensitization, and allodynia. Moreover, deletion of RARα in spinal PV+ neurons or application of an RARα antagonist in the spinal cord prevented the development of SNI-induced mechanical allodynia. Together, our results reveal a molecular mechanism of neuropathic pain whereby homeostatic plasticity causes the mis-direction of tactile information flow to ascending nociceptive pathways following peripheral nerve injury.

Parvalbumin protein controls inhibitory tone in the spinal cord

“…The efficacy of their synaptic connection with their targets could be reduced, through pruning of their terminals, decreased vesicular content of their inhibitory transmitters, or decreased post-synaptic receptors. This hypothesis is supported by a recent study demonstrating that PV neurons lose their inhibitory effect on postsynaptic targets after nerve injury (Cao, Scherrer & Chen, 2022). The mechanisms that cause this reduced inhibition remain unclear.…”

“…Importantly, nearly 80% of WGA-IR neurons were not labeled by PKCg, indicating that PV neurons may have several other targets in the dorsal horn, including the recently reported vertical cells (Boyle et al, 2019). It was recently reported that the inhibitory output of PV neurons onto PKCg neurons was significantly lower in nerve injured mice (Chen, Scherrer & Cao, 2022), further supporting the notion of a disinhibition of postsynaptic targets. In these excitatory neurons, activity of the PKCγ enzyme was shown to be central to their role in mechanical allodynia (Malmberg et al, 1989;Miraucourt, Dallel & Voisin 2007;Petitjean et al, 2015).…”

“…In the mouse, the dorsal horn is comprised of several subsets of inhibitory interneurons involved in modality-specific processing of peripheral inputs (Bourane et al, 2015a; Bourane et al, 2015b; Koch et al, 2017). Multiple reports have highlighted the importance of the inhibitory tone provided by PV neurons (Hughes et al, 2012; Petitjean et al, 2015; Abraira et al, 2017; Cao, Scherrer & Chen, 2022), and modeled their impact on the excitability of dorsal horn circuits (Medlock et al, 2022). Our results suggest that the decrease in PV expression leads to the decrease in PV neuron output.…”

“…This discrepancy between the two models could be due to topographical differences in the termination of these sciatic nerve branches within the mediolateral zones of the dorsal horn (Corder et al, 2010). Although the role of PKCγ in nerve injury-mediated mechanical allodynia is established (Malmberg et al, 1989; Petitjean et al, 2015; Miraucourt, Dallel & Voisin, 2007), as well as their inputs from PV neurons (Petitjean et al, 2015; Boyle et al, 2019; Cao, Scherrer & Chen, 2022), it is possible that the decrease in PV-PKCγ synapses alone may not be the only explanation for the reduced inhibitory output from PV neurons.…”

“…In conclusion, we propose a model in which the incoming inputs from Aβ fibers are prevented from polysynaptically activating lamina I projection neurons because PV neurons receive a copy of this input and can impose it on their post-synaptic targets, whether they are PKCγ neurons (Petitjean et al, 2015; Cao, Scherrer & Chen, 2022; Medlock et al, 2022), vertical cells (Boyle et al, 2019), or the central terminals of Aβ fibers themselves (Hughes et al, 2012; Abraira et al, 2017; Boyle et al, 2019). Such forward inhibitory mechanism is only possible if the firing pattern of PV neurons can match exactly the continuous firing pattern of the Aβ fibers.…”